Vaccines are one of the most successful means to improving human health and protecting against biological warfare attacks, and the success of a vaccine relies on generating long-lived memory T and B cells and plasma cells. However, we still lack protective vaccines against many threatening pathogens, such as HIV, HCV, malaria and several Biodefense Priority Pathogens. Over the past decade significant progress has been made in identifying and characterizing memory T cells, but still little is known about the signals that regulate their development during infection or vaccination. In this proposal, we aim to identify the chief cytokines elicited by different types of adjuvants that regulate memory CD8 T cell development during simple forms of vaccination. Prior work from my lab and others has shown that inflammatory cytokines, such as IL-12, promote effector CD8 T cell expansion and differentiation, but negatively affect memory cell development by inducing effector cell terminal differentiation and a shortened lifespan. Our preliminary data suggest that there are additional inflammatory cytokines that counteract these negative signals to promote memory precursor cell development and longevity. Using dendritic cell (DC) vaccination in combination with two common adjuvants, CpG and LPS, we found LPS induced ~10 times more memory CD8 T cells than CpG. LPS strongly augmented the formation of memory precursor effector cells (MPECs) whereas CpG induced a large proportion of short-lived effector cells (SLECs) that died following vaccination. This data suggests that LPS induces """"""""pro-memory"""""""" signals and IL-6 and IL-10 are amongst the strongest candidates. Here, we will investigate the role of IL-6, IL-10 and STAT3 signaling in MPEC formation and memory cell development during DC vaccination. Furthermore, we will broaden our investigations to analyze a larger panel of TLR agonists during DC immunization to determine their effects on the quantity, quality and ability of memory CD8 T cells to protect against secondary infection of category A, B and C Biodefense Priority Pathogens. This study will help to identify the key signals that promote memory CD8 T cell development to aide in more rational and successful vaccine design.
Memory CD8 T cells are a critical component of adaptive immunity that protect us against infectious disease and even cancer, however the mechanisms for how these cells develop during infection or vaccination are not clear. The ultimate goal of this proposal is to identify which inflammatory cytokines elicited by adjuvants during peptide-pulsed DC vaccination regulate memory precursor cell formation and their long-term survival. We have identified that the cytokine milieu induced by the TLR agonist LPS can preferentially induce memory cell formation, and we aim to pinpoint the """"""""pro-memory"""""""" signals that regulate this process.
|Kaech, Susan M; Cui, Weiguo (2012) Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol 12:749-61|
|Cui, Weiguo; Liu, Ying; Weinstein, Jason S et al. (2011) An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity 35:792-805|